On March 5, 2019, the FDA approved esketamine (Spravato) nasal spray as add-on therapy to traditional antidepressant medications for treatment-resistant depression (TRD). In this article, I will describe the events that led to esketamine’s development, review the data submitted to the FDA, and discuss what the future might hold for esketamine.

Background
Ketamine was first synthesized in 1962 by Parke-Davis Pharmaceuticals with the goal of creating an alternative to the anesthetic agent phencyclidine (PCP), which had become a drug of abuse. Ketamine was approved by the FDA in 1970 for anesthesia, and it remains in use today, in part because it suppresses respiration less than most other anesthetics.

In 2000, Berman et al published the first study (n = 7) suggesting that intravenous ketamine can produce rapid antidepressant effects. Since then, nearly two dozen trials have for the most part replicated these results. Unlike current antidepressants that act primarily on monoamine neurotransmitters, ketamine appears to work by enhancing glutamate transmission through NMDA receptor antagonism.

Although intravenous ketamine appears to be an effective rapid-acting antidepressant, its commercial prospects are limited by the fact that it is available generically and is unlikely to yield the kind of return on investment drug companies need in order to market new products. In order to get around this financial issue, Janssen was able to patent esketamine, which is the ketamine (S)-enantiomer. This is similar to the strategy Forest Pharmaceuticals used many years ago when it successfully marketed citalopram’s (S)-enantiomer: escitalopram (Lexapro).

Esketamine trials
The first published study of esketamine used an intravenous version. It demonstrated rapid and robust antidepressant effects within 2 hours in a ­placebo-controlled trial of 30 subjects (Singh JB et al, Biol Psychiatry 2016;80(6):424–431). With these encouraging results, Janssen next focused on intranasal esketamine. Daly and colleagues randomized 67 TRD patients, who remained on their existing antidepressant, to twice-weekly adjunctive placebo or intranasal esketamine at fixed dosages of 28 mg, 56 mg, or 84 mg. After one week, ­placebo ­non-responders were then ­re-randomized to one of the same four treatment arms. By week 2, all three dosages separated from placebo with a significant dose-response effect (p < 0.001). These gains were maintained over 6 weeks of open-label follow-up treatment (Daly EJ et al, JAMA Psychiatry 2018;75(2):139–148).

Canuso and colleagues next evaluated the benefits of intranasal esketamine 84 mg as add-on therapy to oral antidepressants in hospitalized patients with active suicidal ideation (Canuso CM et al, Am J Psychiatry 2018;175(7):620–630). Here, esketamine showed acute benefits at 4 and 24 hours for both depression and suicidality, though these responses were not maintained through the duration of the 4-week study.

In addition to the studies above, Janssen submitted the results of four pivotal trials to the FDA, though they have not yet been published. These included three short-term, randomized, double-blind trials (a fixed-dose study, a flexible-dose study in adults, and a flexible-dose study in geriatric subjects), and one long-term, double-blind maintenance study.

The findings were generally consistent with the previously published data. To keep things simple, I’ll combine the results of the three short-term TRD trials. Overall response rates after 4 weeks of treatment were significantly higher for esketamine + antidepressant compared to placebo + antidepressant: 53% (199 of 373) vs 37% (102 of 268), respectively. Of the individual studies, however, only one separated statistically from placebo, though the geriatric trial fell just short (p = 0.06).

In the long-term maintenance trial, the median time to relapse in stable responders to esketamine + antidepressant was significantly longer (635 days) than for those randomized to placebo + antidepressant (88 days; p < 0.001).

Other potential uses
While esketamine has only been approved for TRD, pilot studies suggest that ketamine or esketamine could also be useful for bipolar depression, PTSD, OCD, generalized anxiety disorder, social anxiety disorder, and suicidal ideation (Zhang K and Hashimoto K, Expert Rev Neurother 2018;1–10).

Side effects and safety
Esketamine appears to be reasonably well tolerated, with only about 5% of patients discontinuing treatment due to side effects over the course of 1 year of treatment. The most common side effects include a bitter aftertaste, nausea, dizziness, and sedation. Esketamine increases blood pressure on average by 5–10 mm Hg, and this tends to peak about 40 minutes post-dose before gradually resolving. Dissociation (or a sense of feeling drugged) is also commonly reported, though this too tends to dissipate within 1–2 hours.

Risk Evaluation and Mitigation ­Strategy (REMS)
Esketamine is a Schedule III controlled substance; that’s one level below the stimulants and one level above the benzos. It has regulations of its own, however. Providers must register with the REMS system, and the DEA needs to perform an in-person inspection of the provider’s office (www.thecarlatreport.com/REMS). A health care provider needs to provide supervision while the patient self-administers the intranasal dose, and this supervision must continue for at least 2 hours afterward to monitor for hypertension, sedation, and dissociation. Patients are not allowed to drive on treatment days and cannot take the medication home.

TCPR’s Take
Esketamine is the first novel antidepressant introduced in over three decades. It offers a new alternative for TRD and rapid-acting relief for severe depression and suicidality.

So how good is the science? If we consider the entire body of ketamine and esketamine research, it seems impressive. The published trials have mostly yielded significant results, and these studies stand out by including patients with severe depression and suicidal ideation. Another design feature worth noting is that esketamine was initiated at the onset of a new antidepressant trial, whereas most augmentation studies add agents to an ongoing, failed trial. Why should this matter? Because it’s harder to demonstrate that a treatment works when there’s therapeutic “noise” from a new antidepressant that may be offering some therapeutic benefit of its own. In other words, the design of the esketamine trials actually made it harder to demonstrate the drug’s efficacy, so it’s all the more impressive that the agent actually beat placebo.

With an 18% drug-placebo separation in relapse rates, esketamine’s long-term benefits appear comparable to those seen with atypical antipsychotic augmentation (Borges S et al, J Clin Psych 2014;75(3):205–214), though these results need to be replicated.

If there is one drawback to the esketamine research that should temper our enthusiasm, it is the Achilles heel of almost all drug research: side-effect unblinding. Esketamine produces predictable side effects of sedation, dissociation, and a bitter aftertaste. Many patients could probably guess whether they’d been randomized to esketamine and whether it had been withdrawn from them during the maintenance phase. Such unblinding artificially inflates drug-placebo differences (Moncrieff J et al, Br J Psych 1998;172:227–231).

The failure to reach statistical significance in two of the three esketamine studies may be due to their sample sizes, which were smaller than those in most trials submitted to the FDA. Esketamine’s magnitude of effect is similar to or slightly lower than ketamine’s, which implies a larger sample may have produced a positive result. On the other hand, it may be a weakness of the drug itself rather than the study design.

One factor that probably swayed the FDA was our dire need to offer something new for patients suffering from TRD. But caution is warranted. History reminds us that the enthusiasm accompanying novel treatments almost never stands the test of time.